Infection with mouse hepatitis virus type 4 (MHV-4, JHM strain) provides a reproducible experimental model of acute and chronic central nervous system (CNS) demyelination. In susceptible mice, it is characterized by recurrent demyelination. However, unlike other experimental demyelinating disease, there is extensive remyelination by oligodendrocytes, and neither a perivascular nor a prolonged infiltrating mononuclear cell reaction. The proposed studies encompass three overlapping areas to better understand the potential interaction between host genetic control of virus replication and viral cell tropisms, target cell responses to virus infection and remyelination by oligodendrocytes, and their relation to host immune responses. Studying host genetic control, I will test the hypothesis that the single gene locus mapped to mouse chromosome 7, regulates host susceptibility to virus replication by encoding a virus receptor. Although resistant mice lack this receptor on enterocytes, their astrocytes (unlike enterocytes, macrophages and neurons) do support virus replication. I will determine whether the same chromosome 7 locus or a different locus accounts for infection of these glial cells. Studying target cell responses, I will explore the biology of MHV-4 infection of oligodendrocytes and astrocytes in vitro, and compare these to results in vivo, to assess the selective vulnerability of these cell types, and their capacity to remain persistently infected. I will also test the hypothesis that MHV-4 infection of astrocytes can restrict their ability to express class II MHC molecules, which may in turn restrict development of inflammatory responses in the CNS. Finally, I will ask whether remyelination by oligodendrocytes, possibly persistently infected with MHV, reflects a direct effect MHV on the cell or an indirect effect due to the absence of a CNS infiltrate. Studying the host immune responses, I will determine whether MHV infects specific lymphocyte subsets, or limits reactivity to viral or CNS antigens, thereby restricting an infiltrating mononuclear cell response. If present I will test whether passive transfer of these lymphocytes, or those from virus resistant strains of histocompatible mice reactive to MHV or myelin antigens, can alter the pattern of disease. I will also test the alternative hypothesis that the antigen presentation capacity of astrocytes for the CNS is restricted following infection by MHV-4, by testing whether MHV infection can restrict the development of EAE in SJL mice, since SJL astrocytes but not their lymphocytes can be infected by MHV-4.